Process for precursors to calcitriol and related compounds

ABSTRACT

The process of the invention comprises reacting a C-22-halo-23,24-bisnorsteroid or C-22-halo-23,24-bisnor-9,10-secosteroid with a nickel complex of an electron withdrawing alkene of the formula ##STR1## wherein R 1  is hydrogen, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyl or unsubstituted or substituted lower alkyl, and R 2  is hydroxyl, lower alkoxy, or unsubstituted or substituted lower alkyl, 
     to yield a C-25 or C-26 precursor of the formula ##STR2## which is appropriately functionalized for conversion into the corresponding steroid or secosteroid by treatment as hereinafter described.

This is a continuation of application Ser. No. 07/742,796 filed Aug. 9,1991, now abandoned.

BRIEF SUMMARY OF THE INVENTION

The process of the invention comprises reacting aC-22-halo-23,24-bisnorsteroid or C-22-halo-23,24-bisnor-9,10-secosteroidwith a nickel complex of an electron withdrawing alkene of the formula##STR3## wherein R₁ is hydrogen, hydroxycarbonyl, lower alkoxycarbonyl,lower alkylcarbonyl or unsubstituted or substituted lower alkyl, and R₂is hydroxyl, lower alkoxy, or unsubstituted or substituted lower alkyl,

to yield a C-25 or C-26 precursor of the formula ##STR4## which isappropriately functionalized for conversion into the correspondingsteroid or secosteroid by treatment as hereinafter described.

The invention relates to a process for preparing precursors of theformula ##STR5## useful in the preparation of calcitriol and relatedcompounds which comprises reacting a C-22-halo-23,24-bisnorsteroid ofC-22-halo-23,24-bisnor-9,10-secosteroid, further characterized by theformula AX, wherein A is 23,24-bisnorsteroid or a23,24-bisnor-9,10-secosteroid radical and X is halogen, with a nickelcomplex of an electron withdrawing alkene of the formula ##STR6##wherein R₁ is hydrogen, hydroxycarbonyl, lower alkoxycarbonyl, loweralkylcarbonyl or unsubstituted or substituted lower alkyl, and R₂ ishydroxyl, lower alkoxy or unsubstituted or substituted lower alkyl,

to yield a C-25 or C-26 precursor appropriately functionalized forconversion into the corresponding steroid or secosteroid by treatment ashereinafter described.

Preferably, in formulas III and IV, R₁ is hydrogen and R₂ is loweralkoxy or lower alkyl.

As used herein, the term "lower alkyl" denotes a straight or branchedchain saturated hydrocarbon radical containing 1 to 7 carbon atoms,preferably from 1 to 4 carbon atoms, for example, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl and the like. Thelower alkyl group may be substituted by, for example, hydroxyl or loweralkoxy. The term "lower alkoxy" denotes an alkyl ether in which thealkyl group is as described above, for example, methoxy, ethoxy,propoxy, pentoxy, and the like. As further used herein, the term halogenpreferably includes iodine, bromine, and chlorine.

The term "protecting group" denotes a group for protecting a hydroxylgroup which, upon acid catalyzed cleavage, hydrogenolysis ornucleophilic attack yields the free hydroxyl group. Suitable protectinggroups are, for example, tetrahydropyranyl, benzyl, t-butyl or4-methoxy-tetra-hydropyranyl. Other examples include benzyhydryl,trityl, alpha-lower alkoxy-lower alkyl such as methoxymethyl, tri(loweralkyl) silyl, such as, trimethylsilyl, t-butyldiethylsilyl ort-butyldimethylsilyl.

The term "23,24-bisnorsteroid radical" denotes a steroid in which C₂₃and C₂₄ and subsequent carbons are absent from the normal steroid sidechain. The term "23,24-bisnorsecosteroid radical" denotes a steroid inwhich C₂₃ and C₂₄ and subsequent carbons are absent in the normalsteroid side chain, and the C₉ and C₁₀ bond is absent. It is noted thatin said steroids a free hydroxyl is protected for the purposes of thisinvention.

Exemplary of such steroid radicals are: ##STR7## wherein R₃ is hydrogenor OP, and P is hydrogen or a protecting group.

Exemplary of the compounds of formula IV are: ##STR8## wherein R₁, R₂,R₃, A and P are previously described.

The compounds of formulas IVb and IVc also form part of this invention.##STR9## wherein R₁, R₂, A and X are as previously described, and n isan integer from 0 to 6, provided that, when n is 0, a proton source isrequired for the reaction.

In Reaction Scheme I, a compound of formula III, which are knowncompounds or can be prepared according to known procedures, is firstreacted with a nickel (II) salt, for example, nickel acetonylacetonate,a nickel halide, such as, nickel chloride or the like, as its hydrateor, if unhydrate, in the presence of a proton source. This reaction iscarried out in the presence of a reducing agent, such as, an alkalineearth metal or alkali metal, preferably, zinc metal, in an organicsolvent which is also a ligand source, such as, pyridine or a mixture ofsolvents such as pyridine-tetrahydrofuran, pyridine-acetonitrile or thelike, or in an organic solvent, such as, an alcohol, an ether or thelike, and a ligand source, such as, triphenylphosphine or the like,conveniently, at a temperature in the range of 0° C.-150° C. and over aperiod of 5 minutes to 24 hours, to give a nickel complex of thecompound of formula III.

The resulting complex is then treated, in situ, with a compound offormula II, which are known compounds or can be prepared according toknown procedures, in a solvent or mixture of solvents as describedabove, conveniently, at temperature in the range of from 0° C. to 100°C. and over a period of 5 minutes to 24 hours, to give the correspondingcompound of formula IV. The resulting compound of formula IV may beisolated and purified by known standard methods, such as, extractionfollowed by chromatography.

As the proton source, there can be used, for example, water, an ammoniumsalt, a pyridinium salt of the like.

The nickel (II) salt can be used in catalytic to stoichiometricquantities.

Exemplary of the compounds of formula II are compounds of the formulas##STR10## wherein R₃, P and X are as previously described, as well as,1(S),3(R)-Bis(tert-butyldimethylsiloyloxy)-20(S)-(iodomethyl)-9,10-secopregna-5(Z),7(E),10(19)-triene;

1(S),3(R)-Bis-(tert-butyldimethylsilyloxy)-22-iodo-23,24-bisnor-5,7-cholestadiene;

3(R)-(tert-butyldimethylsilyloxy)-20(S)-(iodomethyl)-9,10-secopregna-5(Z),7(E),10(19)-triene;and the like. ##STR11## wherein R₁, R₂, R₃, and P are as previouslydescribed.

In Reaction Scheme II, the conversion of a compound of formula IVb intoa compound of formula IVc can be carried out by the known method ofcheletropic extrusion of sulfur dioxide, preferably by heating in thepresence of a weak base, such as, sodium bicarbonate, or an organicbase, such as, pyridine. The extrusion is carried out in a solvent, suchas, ethanol or pyridine at a temperature in the range of 30° to 100° C.The resulting product of formula IVc is isolated by conventionalmethods, such as, extraction and chromatography.

A compound of formula IVc can be converted into the correspondingcompound of formula IVd by photochemical isomerization using for examplea 450 W medium pressure lamp, conveniently, at a temperature in therange of from 0°-50° C., in the presence of a photosensitizer, such as,9-acetylanthracene or thioxanthen. As solvents for the isomerization, analcohol, such as, methanol, a hydrocarbon, such as hexane, and the likecan be utilized. ##STR12## wherein R₁, R₂, R₃ and P are as describedpreviously, and R₄ is lower alkyl.

In Reaction Scheme III, an end product of formula Ia or Ib can beobtained from the corresponding compound of formula IVc or IVd byreaction with an organometallic reagent, such as, R₄ MgX or R₄ Li,wherein R₄ is lower alkyl and X is halogen, in an ethereal solvent, suchas, diethyl ether or tetrahydrofuran, at a temperature in the range offrom about 0° C. to 70° C.

When P is a protecting group in a compound of formula Ia and Ib,deprotection of a compound of formula Ia leads to a correspondingvitamin D₃ compound. In the case of a compound of formula Ib,deprotection leads to the trans isomer, which can be photoisomerized, asdescribed previously, to give the corresponding vitamin D₃ compound.##STR13## wherein R₁, R₂, R₃, R₄ and P are as previously described.

In Reaction Scheme IV, a compound of formula IVa, which are knowncompounds, which can be converted to the known compounds of formula Ia,as hereinafter described.

Such conversion involves reaction with an organometallic reagentfollowed by photolysis as described, for example, in:

(a) J. Tsuji et al, PCT Int. Appl. WO 9000560 (Jan. 25, 1990); C.A.1990, 112, 217352g;

(b) B. Schoenecker et al, Tetrahedron Letters 1990, 31, 1257; Ger (East)DD 273,065 (Nov. 1, 1989); C.A. 1990, 112, 217351f;

(c) Schoenecker et al, Ger (East) DD 268,956 (Jun. 14, 1989) C.A. 1990,112, 1192426b; and

(d) Fassler et al, Ger (East) DD 272,068 C.A. 1990, 112, 198895t.

The protecting groups can be removed by acid catalyzed cleavage, whichis carried out by treatment with an organic or inorganic acid. Among thepreferred inorganic acids are the mineral acids, such as, sulfuric acid,hydrohalic acid, or the like. Among the preferred organic acids arelower alkanoic acids, such as, acetic acid, paratoluenesulfonic acid, orthe like. The acid catalyzed cleavage can be carried out in an aqueousmedium or in an organic solvent medium. Where an organic acid or alcoholis utilized, the organic acid or alcohol can be the solvent medium. Inthe case of tetrahydropyranyl ethers, the cleavage is generally carriedout in an aqueous medium. In carrying out such cleavage, temperature andpressure are not critical and this reaction can be carried out at roomtemperature.

In the case of nucleophilic cleavage of silyl protecting groups,nucleophilics such as a fluoride, a bromide, an iodide may be usedaccording to known procedures.

The examples which follow further describes the invention. Alltemperatures are given in degrees Centigrade.

EXAMPLE 1 6(R,S)-SO₂ adduct of9,10-seco-3-(tertbutyldimethylsilyloxy)-20-(S)-(iodomethyl)pregna-5(E),7(E),10(19)-triene

To a solution of 50 g of the SO₂ adducts of9,10-seco-3β-(tertbutyldimethylsilyloxy)-20-(S)-(hydroxymethyl)-pregna-5(E),7(E),10(19)-triene,which was prepared according to the method of Hesse (U.S. Pat. No.4,772,433, Sep. 20, 1988) in 580 mL of dichloromethane was added 20.5 gof imidazole and 60 g of triphenylphosphine. The reaction mixture wascooled to -10° C. under argon and 58 g of iodine was added portionwisekeeping the reaction temperature below 10° C., over 20 minutes. Themixture was stirred for 0.5 hour and then the cooling bath was removedand stirring continued for 2 hours; tlc indicated that the reaction wascomplete. 15 mL of ethanol was added and the mixture was stirred for 1hour. To this mixture was then added 15 g of sodium thiosulfatepentahydrate in 10 mL H₂ O to quench the excess iodine, and stirred for0.5 hour. The solvent was removed in vacuo to dryness. The residue wasslurried with 1.0 L of diethyl ether. The ether extract was decanted andthen followed by additional 2×750 mL of ether extracts. The combinedextracts were washed with 750 mL 1:1 brine-H₂ O and then dried (Na₂ SO₄)and evaporated in vacuo to afford 60 g of crude C-22-iodo-SO₂ -adductt-butyldimethylsilyl ether. This was dissolved in 50 mL of 1:1 ethylacetate-hexane and applied to 800 g of silica gel (200-400 mesh) columnpacked in 5% ethyl acetate in hexane. Elution at 4 psi air pressure with10×500 mL of 5% ethyl acetate in hexane, and 10×1.0 L of 10% ethylacetate hexane. Fractions 4-20 were combined and evaporated in vacuo, toafford 50 g (71% yield) of 6(R,S)-SO₂ adduct of9,10-seco-3-(tertbutyldimethylsilyloxy)-20-(S)-(iodomethyl)pregna-5(E),7(E),10(19)-trieneas a light yellow foam. ¹ HNMR (CDCl₃) δ0.05 (6H, Me₂ Si) 0.60/0.69 (3H,CH₃ -18), 0.90 (9H, t-BuSi), 1.02/1.06 (3H, d, J=7 Hz, CH₃ -21),3.20-3.30 (2H, m, CH₂ I), 3.65 (2H, br s, CH₂ SO₂), 4.00 (1H, br s,CHOSi), 4.58 (1H, d of d, J=2 and 7 Hz, CH-6) 4.72 (1H, d of d, J=2 and7 Hz, CH-7).

EXAMPLE 2 6(R,S)-SO₂ adduct of1(S),3(R)-Bis(tert-butyldimethylsilyloxy)-20(S)-(hydroxymethyl)-9,10-secopregna-5(E),10(19)-triene

A mixture of (63.0 g) of the SO₂ adducts [(6S)- and 6(R)] of1(S),3(R)-Bis(tert-butyldimethylsilyloxy)-9,10-secoergosta.5,7(E),10(19),22(E)-tetraene (prepared according to the method ofCalverley, Tetrahedron, 1987, Vol. 43,4609) in 450 mL of CH₂ Cl₂ and 150mL of methane was cooled to -10° C. and ozonized for 10 minutes. Themixture was purged with argon treated with 10.25 g of powdered sodiumborohydride, and then allowed to warm to room temperature. Stirring wascontinued at room temperature for 2.0 hours and the mixture wasconcentrated in vacuo to dryness. The residue was treated cautiouslywith a mixture of 350 mL of hydrochloric acid and 250 mL of ethylacetate. The organic phase was separated, and the aqueous phase wasre-extracted with 250 mL of ethyl acetate. The combined organic extractswere washed with 150 mL of saturated brine, dried (MgSO₄), filtered andevaporated to give 65.4 g of a pale yellow glass. Chromatography of thisover 500 g of silica (230-400 mesh) with 3.6 L of 10% ethyl acetate inhexane, 3.6 L of 15% ethyl acetate in hexane, 5.4 L of 20% ethyl acetatein hexane, and 2 L of 25% ethyl acetate gave 42.64 g (85.5% yield) ofthe desired 6(R,S)-SO₂ adduct of1(S),3(R)-Bis(tertbutyldimethylsilyloxy)-20(S)-(hydroxymethyl)-9,10-secopregna-5(E),7(E),10(19)-triene.A pure sample of the major isomer was obtained as a glass: mp 100°-103°C.; [α]²⁵ D+2.54° (CHCl₃, C=1.026); UV (EtOH) 203 (ε=20,880) nm; IR(CHCl₃) 3625 cm⁻¹ ; ¹ H NMR (CDCl₃) δ0.05 (2×Me₂ Si), 0.65 (3H, s, CH₃-18), 0.85 (2× -t-BuSi), 1.05 (3H,d,J=7 Hz, CH₃ -21), 3.40 (1H, d of d,J=2 and 7 Hz, CH_(A) of CH₂ OH) 3.60 (1H,d,CH_(A) of CH₂ SO₂), 3.65 (1H,d of d, CH_(B) of CH₂ OH), 3.95 (1H, d of d, CH₂ SO₂), 4.20 (1H, br s,CHOSi), 4.37 (1H, d, CH-6), 4.71 (1H, d, CH-7); MS m/z 574 (M-SO₂).Anal. Calcd for C₃₄ H₆₂ O₅ SSi₂ : C,63.90; H,9.98; S,5.02. Found:C,64.29; H,9-93; S,4.75.

EXAMPLE 3 6(R,S)-SO₂ adduct of1(S),3(R)-Bis(tert-butyldimethylsilyloxy)-20(S)-(iodomethyl)-pregna-5(E),7(E),10(19)-triene

A stirred solution of 19.5 g of imidazole and 36.61 g oftriphenylphosphine in 300 mL of dichloromethane was treated with 33.1 gof iodine. The mixture was stirred at 10° C. for 15 minutes and treatedwith a solution of 41.64 g the epimeric alcohols (prepared in Example 2)in 200 mL of methylene chloride. Stirring was continued at roomtemperature for 2.5 hours, and the mixture was filtered. The filtratewas washed with 400 mL of 2% sodium thiosulfate, 200 mL of 0.5Nhydrochloric acid, 200 mL of saturated brine, dried (MgSO₄), andevaporated to give an off-white solid, which was stirred with 400 mL ofether for 15 minutes (to remove triphenylphosphine oxide) and filtered.The filtrate was evaporated to give 53.7 g of crude mixture of 6S and 6Repimeric iodides. Chromatography (under 5 psi pressure) on 475 g ofsilica gel (230-400 mesh) with 1 L of hexane, 3.6 L of 5% ethyl acetatein hexane, and 3.6 L of 10% ethyl acetate in hexane, collecting 200 mLfractions, gave 40.79 g of 6(R,S)-SO₂ adduct of1(S),3(R)-Bis(tert-butyldimethylsilyloxy)-20(S)-(iodomethyl)-pregna-5(E),7(E),10(19)-triene.Pure samples of each of the diastereomers (isomer A and isomer B) wereisolated from the above chromatography and characterized as follows.Isomer A: amorphous solid, mp 78°-82° C., [α]²⁵ D+31.94° (CHCl₃, C=1.00)UV (EtOH) 201 (ε=23,100); ¹ H NMR (CDCl₃) δ0.05 (2×Me₂ Si), 0.70 (3H, s,CH₃ -18), 0.90 (2×t-BuSi), 1.03 (3H, d, J=6 Hz, CH₃ -21), 3.21 (1H, d ofd, CH_(A) of CH₂ I), 3.32, (1 H, d of d, CH_(B) of CH₂ I), 3.61 (1H, d,CH_(A) of CH₂ SO₂), 3.92 (1H, d, CH_(B) of CH₂ SO₂), 4.20 (1H, CHOSi),4.36 (1H, CHOSi), 4.65 (1H, d, CHSO₂), 4.70 (1H, CH-7); MS m/z 552(M-SO₂ -132). Anal. Calcd for C₃₄ H₆₁ IO₄ SSi₂ : C, 54.52; H, 8.21; S,4.28; I, 16.94. Found: C, 54, H, 8.41; S, 4.50; I, 17.19. Isomer B Foam:[α]²⁵ D-12.35° (CHCl₃, C=0.8904); Anal. Calcd. for C₃₄ H₆₁ IO₄ SSi₂ : C,54.52; H, 8.21; S, 4.28; I, 16.94. Found: C, 54.48; H, 8.46; S, 4.38; I,17.23.

EXAMPLE 41(S),3(R)-Bis-(tert-butyldimethylsilyloxy)-20(S)-(hydroxymethyl)-9,10-secopregna-5(E),7(E),10(19)-triene

A 250-mL, round-bottomed flash equipped with a condenser capped with anargon inlet bubbler and containing a magnetic stirrer was charged with5.5 g (8.6 mmol) of alcohol from Example 2 in 56 mL of 95% ethanol (2B)and the mixture was stirred at reflux for 5 hours. It was thenconcentrated under vacuum (water aspirator) to dryness, diluted with 150mL of hexane and filtered. The filter cake was washed some hexane andthe combined filtrate and washing were dried (MgSO₄), filtered andevaporated to give 4.53 g of a thick yellow oil. This waschromatographed on 86 g of flash silica gel (40 μm) packed in hexanewith 2%, 3%, and 5% ethyl acetate in hexane, monitoring the progress ofthe chromatography by TLC (25% ethyl acetate in hexane). The appropriatefractions were combined and the solvents were removed by evaporation togive 1.65 g of1(S),3(R)-bis(tert-butyldimethylsilyloxy)-20(S)-(hydroxymethyl)-9,10-secopregna-5(E),7(E),10(19)-triene as a white solid: mp 116°-117° C., [α]²⁵ D+48.20° (CHCl₃,C=1.114); UV (EtOH) 269 (ε=23,600) nm; IR (CHCl₃) 3625 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.60 (12H, 2×Si(e₂). 0.57 (3H, s, CH₃ -18), 0.86 (9H, s,t-BuSi). 0.90 (9H, s, t-BuSi), 1.06 (3H, d, J=6 Hz, CH₃ -21), 3.40 (1H,d of d, J=11 and 3 Hz, H_(A) of CH₂ OH), 3.66 (1H, d of d, J=11 and 3Hz, H_(B) of CH₂ OH), 4.21 (1H, br, s, CHOSi), 4.53 (1H, br s, CHOSi).4.94 (1H, s, CH-19), 4.99 (1H, s, CH-19), 5.83 (1H, d, J=11 Hz, CH-7),6.45 (1H, d, J=11 Hz, CH-6); MS m/z 574 (M⁺, 5). Anal. Calcd for C₃₄ H₆₂O₃ Si₂ : C, 71.02; H, 10.87. Found: C, 71.04; H, 10.99.

EXAMPLE 51(S),3(R)-Bis-(tert-butyldimethylsilyloxy)-20(S)-(iodomethyl)-9,10-secopregna-5(E),7(E),10(19)-triene

A 100-mL, 3-necked round-bottomed flask equipped with an argon inletbubbler, and addition funnel, and containing a magnetic stirrer bar wascharged with 0.861 g of imidazole, 1.66 g of triphenylphosphine, 20 mLof methylene chloride, and 1.46 g of iodine. The mixture was stirred atroom temperature for 15 minutes, cooled to 10° C. and treated with asolution of 1.65 g of the alcohol from Example 4 in 10 mL of methylenechloride. Stirring was continued at room temperature for 1.5 hours, andthe mixture was filtered. The filter cake was washed with 20 mL ofmethylene chloride and the combined filtrate and washing were washedwith 30 mL of cold (˜10° C.) 0.5N hydrochloric acid, 2×50 mL ofsaturated brine, dried (MgSO₄) and evaporated to give a semi-solid. Thiswas slurried with 50 mL of ether, filtered (to remove triphenylphosphineoxide), and the filtrate was concentrated in vacuo to give 2.74 g of agum. Flash chromatography over 45 g of silica (40 μm), which was packedin hexane, collection of the appropriate fractions, and evaporation gavea gum which was dried under high vacuum (0.2 mm Hg) to give 1.72 g of1(S),3(R)-bis-(tert-butyldimethyisilyloxy)-20(S)-(iodomethyl)-9,10-secopregna-5(E),7(E),10(19)-triene as a foam [α]²⁵ D+24.99° (CHCl₃, C=1.0682) UV (EtOH) 267(ε=21,600) nm; ¹ H NMR δ0.05 (12H, 2×SIMe₂), 0.58 (3H, s, CH₃ -18), 0.90(18H, (2×t-BuSi), 1.05 (3H, d, J=6 Hz, CH₃ -21), 3.20 (1H, d of d,CH_(A) of CH₂ I), 3.33 (1H, d, CH_(B) of CH₂ I), 4.22 (1H, br s, CHOSi),4.55 (1H, br s, CHOSi), 4.94 (1H, s, CH_(A) of CH₂ -19), 4.99 (1H, s,CH_(B) of CH₂ -19), 5.82 (1H, d, J=12 Hz, CH-7), 6.47 (1H, d, J=12 Hz,CH-6).

EXAMPLE 63β-(Isopropyldimethylsilyloxy)-22-iodo-23,24-bisnor-cholesta-5-ene

To a stirred solution of 2.5 g of3β-(Isopropyldimethylsilyloxy)-22-hydroxy-23,24-bisnorcholesta-5-ene in50 mL methylene chloride was added 2.62 g (10 mmol) oftriphenylphosphine, 2.54 g (10 mmol) of iodine, and 1.02 g (15 mmol) ofimidazole. The mixture was stirred at room temperature for 1.5 hours,concentrated and the residue was diluted with diethyl ether. Filtrationand evaporation of the filtrate gave 3.5 g3β-(Isopropyldimethylsilyloxy)-22-iodo-23,24-bisnor-cholesta-5-ene,which was used without further purification in the next step (Example7).

EXAMPLE 7 Ethyl3β-(Isopropyldimethylsilyloxy)-26,27-bisnor-cholesta-5-ene-25-oate

A mixture of 0.65 g of zinc powder, 1.2 g of nickel chloridehexahydrate, and 2.0 g (20 mmol) of ethyl acrylate in 10 mL of a 1:1mixture of pyridine and tetrahydrofuran was stirred under argon at 65°C. for 30 minutes and then cooled to 35° C. A solution of 3.5 g of theiodide from Example 6 in 10 mL of a 1:1 mixture of pyridine andtetrahydrofuran was then added to the reaction mixture during 5 minutes.The mixture was stirred at 35° C. for 2 hours and then diluted with 100mL of ethyl acetate. The mixture was washed with 2×50 mL of a solutionconsisting of 8% EDTA and 8% sodium bicarbonate, 2×50 mL of saturatedbrine, dried (Na₂ SO₄), filtered and evaporated to give a gum, which waspurified by chromatography over silica gel to give ethyl3β-(Isopropyldimethylsilyloxy)-26,27 -bisnor-cholesta-5-ene-25-oate: IR(CHCl₃) 1725 (ester) cm⁻¹ ; ¹ H NMR (CDCl₃) δ0.03 (Me₂ Si) 0.65 (s, CH₃,CH₃ -18), 0.72 (6H, s, 2×CH₃), 0.85 (6H, d, Me₂ CH), 0.92 (d, CH₃ -21)0.95 (3H, s, CH₃ -19), 1.25 (CH₃, t, J=7 Hz) 3.48 (1H, m, CH-3), 4.11(2H, q, J=7 Hz, CH₂ O), 5.3 (1H, d, J=2 Hz, CH-6).

EXAMPLE 81α,3β-Bis(tertbutyldimethylsilyloxy)-22-iodo-23,24-bisnor-cholesta-5-ene

A solution of 3.0 g of1α,3β-bis(tertbutyldimethylsilyloxy)-22-(p-tolysulfonyloxy)-23,24-bisnor-cholesta-5-ene,prepared from the corresponding C₂₂ alcohol in 17 mL of acetone and 8 mLof dimethylsulfoxide was treated with 1.5 g of sodium iodide and themixture was stirred at reflux for 18 hours. It was cooled to roomtemperature, diluted with 30 mL of water, and extracted with 70 mL ofethyl acetate. The combined extracts were washed with 2×50 mL ofsaturated brine, dried (MgSO₄), and evaporated to give 2.75 g of asolid, which was crystalized from a mixture of ether-methanol (1:2) togive1α,3β-bis(tertbutyldimethylsilyloxy)-22-iodo-23,24-bisnor-cholesta-5-eneas colorless crystals, mp 144°-146° C.; [α]_(D) +20.38° (CHCl₃,C=0.927). Anal. Calcd. for C₃₄ H₆₃ IO₂ Si₂ : C, 59.45; H, 9.24; I,18.47. Found: C, 59.54; H, 9.29 ; I, 18.17.

EXAMPLE 9 Ethyl1α,3β-Bis-(tert-butyldimethylsilyloxy)-26,27-bisnorcholesta-5-ene-25-oate

A stirred mixture of 250 mg of nickel chloride hexahydrate 350 mg ofzinc dust and 0.5 mL of ethyl acrylate in 1.5 mL of tetrahydrofuran and1.0 mL of pyridine was stirred at 60° C. for 25 minutes and then cooledto room temperature. To the resulting brick-red mixture was added 500 mgof the iodide in 2 mL of tetrahydrofuran and stirring was continued atroom temperature overnight followed by heating at 50° C. for 4 hours.The mixture was diluted with 75 mL of ethyl acetate and filtered overCelite, and the filtrate was washed with 2×25 mL of saturated brine,dried (MgSO₄) and evaporated to give 540 mg of a gum. Chromatography ofthis over 20 g of silica gel (70-230 mesh) with 25% ethyl acetate inhexane followed by crystallization from ether-methanol to give ethyl1α,3β-Bis-(tert-butyldimethylsilyloxy)-26,27-bisnor-cholesta-5-ene-25-oate330 mg (68.5% yield), mp 97°-100° C.; [α]²⁵ D+13.48° (CHCl₃, C=0.986).Anal. Calcd for C₃₉ H₇₂ O₄ Si₂ : C, 70.85; H, 10.98. Found: C, 70.47; H,10.85.

EXAMPLE 10 6(R,S)-SO₂ adduct of Ethyl3(R)-(tertbutyldimethylsilyloxy)-9,10-seco-26,27-bisnor-cholesta-5(E),7(E),10(19)-trien-25-oate

A 500 mL three-neck flask equipped with a magnetic stirrer, and gasbubbler was charged with 13.1 g of zinc dust. To this was added 60 mL ofa 1:1 mixture of tetrahydrofuran-pyridine, and 9.5 g of nickel chloridehexahydrate and 19.5 mL of ethyl acrylate. This mixture was then heatedto 65° C. while being stirred under argon for 30 minutes to afford areddish brown solution. The mixture was cooled to 30° C. and a solutionof 50 g of the C-22-iodo SO₂ adduct t-butyldimethylsilyl ether (fromExample 1) in 1:1 THF-pyridine was added over 1 hour at a rate so as tomaintain the reaction temperature below 45° C. The mixture was stirredat ambient temperature for 2.5 hours. TLC (7:3 hexane-ethyl acetate)indicated that the reaction was complete. The mixture was filteredthrough a Celite pad and rinsed with 2×100 mL of ethyl acetate. Thefiltrate was concentrated to a third volume and then 1.5 L ethyl acetateadded. This was then washed with 4×100 mL of EDTA solution (80 g EDTA/80g NaHCO₃ diluted to 1.0 L), 2×100 mL of 1:1 brine-water, 2×100 mLsaturated brine, dried (Na₂ SO₄), evaporated in vacuo to afford 39 g(83% yield) of 6(R,S)-SO₂ adduct of ethyl3(R)-(tertbutyldimethylsilyloxy)-9,10-seco-26,27-bisnor-cholesta-5(E),7(E),10(19)-trien-25-oate.This material was used as such in the next step without furtherpurification.

EXAMPLE 11 Ethyl(3R)-(tertbutyldimethylsilyloxy)-9,10-seco-26,27-bisnor-cholesta-5(E),7(E),10(19)-trien-25-oate

39 g of C-25-ethyl ester SO₂ adduct t-butyldimethylsilyl ether (fromExample 10), 35 g of sodium bicarbonate and 500 mL of 95% ethanol washeated at reflux under argon for 2 hours. After cooling, the insolubleswere removed by filtration and rinsed with 2×150 mL of EtOAc. Thefiltrate and washings were evaporated and the residue was taken up in1.0 L of ethyl acetate. This was washed with 3×500 mL of 1:1 brine-waterand 500 mL of brine, dried (Na₂ SO₄), and evaporated to dryness toafford 43 g of crude product. This was dissolved in 30 mL of ethylacetate and applied to 80 g of flash silica (200-400 mesh) pre-packed in5% ethyl acetate in hexane. Elution at 4 psi air pressure with 10×500 mLof 5% ethyl acetate in hexane (TLC in 4:1 hexane/EtOAc). Fractions 4-7were combined and evaporated in vacuo, and finally at 0.5 mm Hg for 2hours, to afford 31 g (89%) yield of ethyl(3R)-(tertbutyldimethylsilyloxy)-9,10-seco-26,27-bisnor-cholesta-5(E),7-(E),10(19)-trien-25-oateas a colorless oil. ¹ H NMR (CDCl₃) δ0.05 (6H, SiMe₂), 0.55 (3H, s, CH₃-18), 0.93 (9H, s, t-BuSi), 0.95 (3H, d, J=7 Hz, CH₃ -21), 1.26 (3H, t,J=7 Hz, CH₃ of ester), 3.82 (1H, m, CH-3), 4.12 (2H, q, J=7 Hz, CH₂ ofester), 4.64 (1H, s, CH_(A) -19), 4.92 (1H, s, CH_(B) -19), 5.84 (1H, d,J=12 Hz, CH-7), 6.45 (1H, d, J=12 Hz, CH-6).

EXAMPLE 12 6(R,S)-SO₂ adduct of Ethyl1(S),3(R)-Bis(tertbutyldimethylsilyloxy)-9,10-seco-26,27-bisnorcholesta-5(E),7(E),10(19)-trien-25-oate

Procedure A: 250-mL, 3-necked round-bottomed flask equipped with amechanical stirrer, argon inlet, and a condenser was charged with 17.23g (0.263 mol) of zinc dust, 40 mL of 1:1 pyridine/tetrahydrofuran (theTHF was distilled under argon from sodium benzyphenone ketyl), 12.78 gof pulverized nickel chloride hexahydrate and 25.8 mL of ethyl acrylate.The stirred mixture was heated to 65°-70° C. for 30 minutes to give anorange-colored mixture, cooled to room temperature and treated with asolution of 40.0 g of the C-22 iodides (from Example 3) in 40 mL of 1:1pyridinetetrahydrofuran. The mixture was stirred at 45° C. for 1.5hours. As TLC (1:4 ethyl acetate/hexane) showed only ca. 50% conversionof iodides into products, 4.0 g of nickel chloride hexahydrate and 5.0mL of ethyl acrylate were added. Stirring was continued at 45° C. for afurther 3.5 hours and the reaction mixture was stored under argon at 0°C. overnight (18 hours). It was diluted with 70.0 mL of ethyl acetateand filtered through Celite, which was washed with 3×100 mL portions ofethyl acetate. The combined filtrate and washings were washed with 200mL ice-cold 1N hydrochloric acid, 3×250 mL, of saturated brine (someemulsion), dried (MgSO₄), filtered and evaporated to give 40.7 g of6(R,S)-SO₂ adduct of ethyl1(S),3(R)-bis(tertbutyldimethylsilyloxy)-9,10-seco-26,27-bisnorcholesta-5(E),7(E),10(19)-trien-25-oateas a foam. TLC (silica gel, 1:1 ethyl acetate-hexane) showed the desiredproducts at Rf 0.57 and Rf 0.45. The starting iodides had Rf 0.71 and Rf0.51. The mixture of crude esters was converted directly into the trieneas described in Example 13A. In a separate experiment, a batch ofisomeric mixture of esters (3.3 g) in 10 mL of 5% ethyl acetate inhexane was purified by chromatography over 60 g of flash silica gel (40μm) packed in 5% ethyl acetate and eluted with 10% ethyl acetate inhexane collecting 30 mL fractions. Isomer A(1.7 g) appeared in fractions14-22, whereas, pure isomer B appeared in fractions 31-42 (437 mg). Theprogress of the chromatography was monitored by TLC (20% ethyl acetatein hexane). Isomer A: This was obtained as an amorphous solid: mp68°-70° C.; [α]_(D) +19.09° (CHCl₃, C=0.958); UV 202 (ε=22210), 266(ε=230) nm; IR (CHCl₃) 1722 cm⁻¹ ; ¹ H NMR (CDCl₃) δ0.05 (12H, 2×Me₂Si), 0.64 (3H, s, CH₃ -18), 0.85 (18H, 2×t-BuSi), 0.95 (3H, d, J=6 HZ,CH₃ -21), 1.25 (3H, t, CH₃ of ester), 3.61 (1H, d, J=12 Hz, CH_(A) ofCH₂ SO₂), 3.95 (1H, d, J=12 Hz, CH_(B) of CH.sub. 2 SO₂), 4.12 (2H, q,J=7 Hz, CH₂ O of ester), 4.18 (1H, br s, CHOSi), 4.36 (1H, br s, CHOSi),4.65 (2H, q, CH-7+CH-6); MS 658 (M-SO₂). Isomer B; This was obtained asa gum, [α]_(D) -19.76° (CHCl₃, C=0.6830). Procedure B; A 100-mL,3-necked, round-bottomed flask equipped with a mechanical stirrer,thermometer, and condenser capped with an argon inlet bubbler wascharged with 20 mL of pyridine, 2.38 g of pulverized nickel chloridehexahydrate, 3.27 g zinc dust and 4.88 mL of ethyl acrylate. The mixturewas stirred at 60° C. under argon for 30 minutes whereupon it becamedeep red. It was cooled to room temperature (23° C.) and treated with asolution of 7.49 g of iodides (from Example 3) 10 mL of pyridine. Aslight exotherm (23° C.→28° C.) ensued. The mixture was stirred at roomtemperature for 2.5 hours, diluted with 50 mL of ethyl acetate andfiltered over Celite. The Celite was washed with 100 mL of ethyl acetateand the combined filtrate and washings were washed sequentially with 100mL of saturated brine: water (1:1), 200 mL of 1.0N hydrochloric acid,100 mL of 1.0N hydrochloric acid, 100 mL of saturated brine, dried(MgSO₄), filtered and evaporated to give 7.22 g of a pale yellow foam.Chromatography of this on 95 g of silica gel packed in hexane, andelution and elution with 3% ethyl acetate in hexane then 5% ethylacetate in hexane with monitoring of the chromatography by TLC, gave,after evaporation of the solvents, 5.28 g of 6(R,S)-SO₂ adduct of ethyl1(S),3(R)-bis(tertbutyldimethylsilyloxy)-9,10-seco-26,27-bisnorcholesta-5(E),7(E),10(19)-trien-25-oate.

EXAMPLE 13 Ethyl1(S),3(R)-Bis(tert-butyldimethylsilyloxy)-9,10-seco-26,27-bisnorcholesta-5(E),7(E),10(19)-triene-25-oate

A. A 1-L, 3-necked, round-bottomed flask equipped with a mechanicalstirrer and a condenser capped with an argon inlet bubbler was chargedwith 39.2 g of the crude mixture of esters and (from Example 12) in 300mL of 95% 2B alcohol and 20.4 g of sodium bicarbonate. The mixture wasstirred at reflux for 2.25 hours, cooled to ca. 45° C. and concentratedin vacuo. 100 mL of ethyl acetate followed by 250 mL of hexane wereadded, and the mixture was stirred for 30 minutes. It was filtered andthe filter cake was washed with 2×50 mL of hexane. The combined filtrateand washings were evaporated to give 36.8 g of a yellow semi-solid. Thiswas dissolved in some hexane and applied to a column of 380 g of silicagel 60 (230-400 mesh) and eluted with 1%, 3%, 5%, and 10% methylenechloride in hexane to remove some less polar impurities as revealed byTLC (1:1 CH₂ Cl₂ in hexane), and finally with 10% ethyl acetate inhexane to give, after collection of the appropriate fractions(ascertained by TLC, 50% CH₂ Cl₂ in hexane) and evaporation (wateraspirator then high vacuum) 20.73 g of ethyl1(S),3(R)-bis(tert-butyldimethylsilyloxy)-9,10-seco-26,27-bisnorcholesta5(E),7(E),10(19)-triene-25-oate as a colorless, waxy solid: mp 69°-71° C.; [α]²⁵D+51.35° (CHCl₃, C=0.9192). UV (EtOH) 268 (ε=24220) nm; IR (CHCl₃) 1725,835 cm⁻¹ ; MS m/z (M⁺, 12). Anal. Calcd for C₃₉ H₇₀ O₄ Si₂ ; C, 71.06;H, 10.70. Found: C, 71.19; H, 10.95.

B. A 50-mL, round-bottomed flask equipped with a condenser capped withan oxygen inlet bubbler, addition funnel, and containing a magneticstirrer bar was charged with 550 mg of nickel chloride hexahydrate, 10mL of pyridine, 760 mg of zinc powder, and 1.16 mL ethyl acrylate. Themixture was stirred at 55°-60° C., ca. 5 mg of iodine was added, andstirring was continued at 55°-60° C. for 20 minutes to give a dark redheterogeneous mixture. It was cooled to 40° C., and treated with asolution of 1.59 g of the iodide from Example 5 in 5 mL of pyridine,stirred at room temperature for 45 minutes, and diluted with 60 mL ofethyl acetate. The mixture was filtered over Celite, and the filtratewas washed with 50 mL of water, 50 mL of 1.0N hydrochloric acid, 50 mLof saturated brine, dried (MgSO₄), filtered, and evaporated to give agum. Flash chromatography of which ever 25 g of silica with 1% ethylacetate in hexane gave, after collection of the appropriate fractionsand evaporation, 1.18 g (77%) of ethyl1(S),3(R)-bis(tertbutyldimethylsilyloxy)-9,10-seco-26,27-bisnorcholesta5(E),7(E),10(19)-triene-25-oate as a gum, identical with the sample fromExample 13 A.

C. 31 g of the compound from Example 11 dissolved in 280 mL of(1:1)methanol-dichloromethane, 13.8 g of N-methylmorpholine-N-oxide and2.30 g of selenium dioxide was heated at reflux under argon for 5 hours.The mixture was cooled and concentrated in vacuo to one third of thevolume. Then 1.0 L ethyl acetate was added, and the mixture was washedwith 3×500 mL=1.5 L of 1:1 brine-water and 500 mL brine, dried (Na₂ SO₄)and evaporated to dryness to afford 33 g of a crude mixture whichdissolved in 500 mL dichloromethane and treated with 6.1 g imidazole and9.8 g of t-butyldimethylsilyl chloride. The mixture was stirred at roomtemperature under argon for 16 hours. The insolubles were filtered off,rinsed with 2×150 mL of dichloromethane and the filtrate and washingswere evaporated to dryness. The residue was taken up in 1.0 L of ethylacetate and washed with 3×500 mL of 1:1 brine water and 500 mL of brine,dried (Na₂ SO₄) and evaporated in vacuo, and finally at 0.5 mm Hg for 2hours, to afford 38.6 g crude product. This was dissolved in 50 mLdichloromethane-hexane (1:2) and applied to 400 g of flash silica gel(200-400 mesh) pre-packed in dichloromethane hexane (1:2). Elution at 4psi air pressure with 20×250 mL of 1:2 dichloromethane hexane followedby 4×500 mL of 3:1 dichloromethane hexane. Fractions 7-20 were combinedand evaporated in vacuo, finally at 0.5 mm Hg affording 15.85 g (41%yield over 2 steps) of ethyl1(S),3(R)-bis(tertbutyldimethyl-silyloxy)-9,10-seco-26,27-bisnorcholesta-5(E),7(E),10(19)-triene-25-oateas a colorless amorphous solid, identical with the samples prepared inExamples 13 A and 13 B.

EXAMPLE 14 6(R,S)-SO₂ adduct of3(R)-tertbutyldimethyl-silyloxy-25-keto-9,10-seco-27-norcholesta-5(E),7(E),10(19)-triene

A 100-mL three-necked flask equipped with a magnetic stirrer and a gasbubbler was charged with 2.24 g of zinc dust suspended in 16 mL of 1:1mixture of tetrahydrofuran-pyridine. To this suspension were added 4.10g of nickel chloride hexahydrate and 3.0 mL of methyl vinyl ketone whilethe reaction mixture was slowly heated to 65° C. After 30 minutes ofheating at 65° C., the mixture was cooled to 35° C. and a solution of10.6 g of C-22-iodo SO₂ adduct t-butyldimethylsilyl ether from Example 1in 12 mL of 1:2 mixture of tetrahydrofuran-pyridine was added over a 10minute period. The reaction mixture was stirred for 2 hours at ambienttemperature. TLC (7:3 hexane-ethyl acetate) indicated that the reactionwas complete. The mixture was diluted with 250 mL ethyl acetate andfiltered through a Celite pad using a sintered glass funnel. Thefiltrate was washed with 3×100 mL=300 mL EDTA solution (80 g EDTA+80 gNaHCO₃ diluted to 1.0 L), 2×100 mL=200 mL 1:1 brine-water, dried (Na₂SO₄), evaporated in vacuo on the rotary evaporator, finally at 0.5 mm Hgfor 2 hours to afford 11 g of crude 6(R,S)-SO₂ adduct of3(R)-tertbutyldimethyl-silyloxy-25-keto-9,10-seco-27-norcholesta-5(E),7(E),10(19)-trienewhich was used directly in the next step (Example 15).

EXAMPLE 153(R)-tert-Butyldimethylsilyloxy-25-keto-9,10-seco-7-norcholesta-5(E),7(E)10(19)-triene

A mixture of 11.0 g of C-25-ketone SO₂ -t-butyldimethylsilyl ether fromExample 14, 4.1 g of sodium bicarbonate, and 55 mL of 95% ethanol wasrefluxed under argon for 2 hours. TLC (9:1 hexane-ethyl acetate)indicated that the reaction was complete. The reaction mixture wasdiluted with 250 mL of ethyl acetate and washed with 3×100 mL of 1:1brine-water and 2×100 mL=200 mL of brine, dried (Na₂ SO₄), andevaporated to dryness. The crude residue was chromatographicallypurified to afford 5.35 g (62% yield for the two steps) of3(R)-tert-Butyldimethylsilyloxy-25-keto-9,10-seco-27-norcholesta-5(E),7(E),10(19)-triene.

EXAMPLE 161(S,R)-Hydroxy,3(R)-tertbutyldimethylsilyloxy-25-keto-9,10-seco-27-norcholesta-5(E),7(E),10(19)-triene

2.35 g of the C-25-ketone trans-triene t-butyldimethylsilyl ether, fromExample 15 in 1.10 g of N-methylmorpholine-N-oxide, and 0.26 g ofselenium dioxide were dissolved in 30 mL of (1:1) mixture ofmethanol-dichloromethane. The mixture was heated at reflux under argonfor 2 hours and tlc (4:1 hexane-ethyl acetate) indicated that thereaction was complete. The reaction mixture was then concentrated to onethird of its volume, diluted with 150 mL ethyl acetate and washed with3×125 mL=375 mL of 1:1 brine-water, 125 mL of brine, dried (Na₂ SO₄),evaporated to dryness, and finally at 0.5 mm Hg to afford 2.4 g crudemixture of 1(S,R)-hydroxy,3(R)-tertbutyldimethylsilyloxy-25-keto-9,10-seco-27-norcholesta-5(E),7(E),10(19)-triene which was used as such in the next step. (Example17).

EXAMPLE 171(S),3(R)-Bis(tertbutyldimethylsilyloxy)-25-keto-9,10-seco-27-norcholesta-5(E),7(E), 10(19)-triene

A crude mixture (2.4 g) of 1α- and 1β-hydroxy compounds from Example 16in 50 mL of dichloromethane, was treated with 0.5 g of imidazole and 0.9g of t-butyldimethylsilyl chloride. The mixture was stirred at roomtemperature under argon overnight. The insolubles were filtered off,rinsed with 2×50 mL of dichloromethane, and evaporated to dryness. Theresidue was dissolved in 125 mL of ethyl acetate, washed with 3×50 mL of1:1 brine-water, 50 mL of brine, dried (Na₂ SO₄), evaporated in vacuo,and finally at 0.5 mm Hg for 2 hours to afford 2.9 g of crude product.This was dissolved in 3 mL of dichloromethane-hexane (1:1) and appliedto 300 g of Baker flash silica gel (200-400 mesh) pre-packed indichloromethane-hexane (1:1). Elution at 4 psi air pressure with 30×125mL of 1:1 dichloromethane-hexane followed by 16×125 mL of 2:1dichloromethane-hexane. Fractions 18-29 were combined and evaporated invacuo, finally at 0.5 mm Hg afforded 1.03 g (35% yield over 2 steps) of1(S),3(R)-bis(tertbutyldimethylsilyloxy)-25-keto-9,10-seco-27-norcholesta-5(E),7(E),10(19)-triene. This was converted into1(S),3(R)-bis(tert-butyldimethylsilyloxy)-9,10-seco-25-hydroxy-cholesta-5(E),7(E),10(19)-trienewith methyl magnesium bromide as described in Example 19.

EXAMPLE 18 Ethyl1(S),3(R)-Bis(tert-butyldimethylsilyloxy)-9,10-seco-26,27-bisnorcholesta-5(Z),7(E),10(19)-trien-25-oate

A 1-L photochemical reactor was charged with a solution of 913 mg ofester from Example 13 and 16-7 mg of 9-acetyl-antharcene in 1.0 L ghexane. With argon bubbled through it, the solution was cooled to 0°-5°C., and was irradiated with a 450 W medium pressure lamp for 45 minutes.The solution was concentrated to give 925 mg of ethyl1(S),3(R)-bis(tert-butyldimethylsilyloxy)-9,10-seco-26,27-bisnorcholesta-5(Z),7(E),10(19)-trien-25-oate:¹ H NMR (CDCl₃) δ0.05 (12H, 2×Me₂ Si), 0.55 (3H, s, CH₃ -18), 0.85 (18H,2×t-BuSi), 0.95 (3H, d, J=6, CH₃ -21), 1.21 (3H, t, J=7 Hz, CH₃ ofester), 4.10 (2H, q, CH₂ of ester), 4.16 (1H, br s, CHOSi), 4.39 (1H, brs, CHOSi), 4.88 (1H, s, CH_(A) -19), 5.18 (1h, s, CH_(B) -19), 6.0 (1H,d, J=11 Hz, CH-7), 6.24 (1H, d, J=11 Hz, CH-6). This material wasreacted with methylmagnesium bromide using conditions in Example 19, andthe derived alcohol was desilylated with tetrabutylammonium fluorideusing conditions defined in Example 21 to give calcitriol.

EXAMPLE 191(S),3(R)-Bis(tert-butyldimethylsilyloxy)-9,10-seco-25-hydroxy-cholesta-5(E),7(E),10(19)-triene

15.85 g of ester from Example 13 dissolved in 75 mL of drytetrahydrofuran (distilled over Na benzophenone ketyl) was cooled in anice bath. To the stirred solution was added 20 mL (0.060 mole) of methylmagnesium bromide (3.0M in ether) over 5 minutes. The mixture wasstirred for 15 minutes. The ice bath was removed and stirring continuedat ambient temperature for 3 more hours. The zero mixture was cooled to0° C. and carefully quenched with 8 mL of saturated ammonium chloride.This mixture was diluted with 800 mL of ethyl acetate, and then washedwith 3×250 mL of 1:1 brine water and 250 mL of brine, dried (Na₂ SO₄),and evaporated in vacuo to afford 15.8 g of crude product. This wassubsequently dissolved in 15 mL of ethyl acetate and applied to a 350 gof flash silica gel (200-400 mesh) column pre-packed in 4:1 hexane ethylacetate. Elution at 4 psi air pressure with 15×125 mL=2.25 L of 4:1hexane-ethyl acetate. Fractions 5-13 were combined and evaporated invacuo and finally at 0.5 mm Hg for 2 hours to afford 12.7 g (82% yield)of1(S),3(R)-bis(tert-butyldimethylsilyloxy)-9,10-seco-25-hydroxy-cholesta-5(E),7(E),10(19)-trieneas a colorless foam. [α]²⁵ D+35.14°; UV (EtOH), 269 (ε=22,520) nm; IR(CHCl₃) 3605 and 1730 cm⁻¹ ; ¹ H NMR (CDCl₃) δ0.05 (12H, 2×Me₂ Si), 0.55(3H, s, CH₃ -18), 0.85 (9H, s, t-BuSi), 0.90 (9H, s, t-BuSi), 0.95 (3H,d, J=7 Hz, CH₃ -21), 4.22 (1H, br s, CH OSi), 4.55 (1H, br s, CHOSi),4.93 (1H, s, CH_(A) -19), 4.99 (1H, s, CH_(B) -19), 5.82 (1H, d, J=11Hz, CH-7), 6.46 (1H, s, CH-6); MS m/z 644 (1, M⁺).

EXAMPLE 201(S),3(R)-Bis(tert-butyldimethylsilyloxy)-9,10-seco-25-hydroxy-cholesta-5(Z),7(E),10(19)-triene

12.5 g (0.0194 mole) of alcohol from Example 19 dissolved in 800 mL ofmethanol containing 3 mL of triethylamine and 630 mg of thioxanthen assensitizer, was irradiated using a 450 Watt Hanovia lamp for 2 hours.The reactor was emptied and rinsed with 2×100 mL=200 mL of methanol. Themixture was evaporated in vacuo. The residue was dissolved in 100 mL of1:1 dichloromethane-ethyl acetate, concentrated to a third volume, andapplied to a 500 g flash silica gel (200-400 mesh) column packed in 4:1hexane-ethyl acetate. The column was eluted at 4 psi air pressure with20×125 mL of 4:1 hexane-ethyl acetate. Fractions 7-15 were combined,evaporated in vacuo to dryness, finally at 0.5 mm Hg for 2 hours toafford 11.7 g (93% yield) of1(S),3(R)-bis(tert-butyldimethylsilyloxy)-9,10-seco-25-hydroxy-cholesta-5(Z),7(E),10(19)-trieneas a colorless amorphous solid. ¹ H NMR (CDCl₃) δ0.05 (12H, 2×Me₂ Si),0.55 (3H, s, CH₃ -18) 0.85 (18H, 2×t-BuSi), 0.92 (6H, s, CH₃ -26+CH₃-27), 4.20 (1H, br s, CHOSi), 4.38 (1H, br s, CHOSi), 4.84, (1H, s,CH_(A) -19), 5.8 (1H, s, CH_(B) -19), 6.04 (1H, d, J=11 Hz, CH-7), 6.24(1H, d, J=11 Hz, CH-6).

EXAMPLE 211(S),3(R),25-Trihydroxy-9,10secholesta-5(E),7(E),10(19)-triene

A 1-L, 3-necked, round-bottomed flash equipped with a mechanical stirrerand argon inlet was charged with a solution of 19.01 g of the compoundfrom Example 19 in 50 mL of anhydrous tetrahydrofuran and 337 mL of a1.0 molar solution of tetrabutylammonium fluoride. The solution wasstirred at room temperature for 5.5 hours, concentrated in vacuo at 45°C., and the resulting thick amber colored oil, which was partitionedbetween a mixture of 500 mL of ethyl acetate and 500 mL of a 1:1water-saturated brine. The organic phase was separated, and the aqueousphase was extracted with 2×250 mL of ethyl acetate. The combined organicextracts were washed with 3×250 mL of 1:1 water-saturated brine, dried(MgSO₄), and carefully evaporated at 50° C. to give 16.06 g of anoff-white solid. This was slurried with 100 mL of 30% ethyl acetate inhexane left at 0° C. overnight and the product was collected byfiltration. It was washed with 3×20 mL 50% ethyl acetate in hexane, anddried in vacuo to give 9.94 g (81%) of1(S),3(R),25-trihydroxy-9,10-secocholesta-5(E),7(E),10(19)-triene: mp170°-173° C.; [α]D+164.39° (CHCl₃, c=0.925).

EXAMPLE 22 1α,25-Dihydroxycholecalciferol(Calcitriol)

A. From1α,3β-Bis(tertbutyldimethylsilyloxy)-9,10-seco-25-hydroxycholesta-5(Z),7(E),10(19)-triene.To a solution of 11.5 g of alcohol from Example 20 in 25 mL oftetrahydrofuran (distilled over Na benzophenone ketyl) was added asolution of 41 mL of tetrabutylammonium fluoride (1.0M in THF). Thereaction mixture was stirred at 45° C. for 4 hours under argon. TLC (3:7hexane-EtOAc) indicated the reaction was complete. The mixture wasevaporated in vacuo to dryness. The residue was taken up in 600 mL ofethyl acetate and washed with 3×200 mL of 1:1 brine-water and 200 mL ofbrine, dried (Na₂ SO₄) and evaporated in vacuo to afford 12.0 g of crudeproduct. This was dissolved in 15 mL of 3:7 hexane-ethyl acetate andapplied to 200 g flash silica gel (200-400 mesh) column packed in 3:7hexane-ethyl acetate. Elution with 24×125 mL 3:7 hexane-ethyl acetate,and 2×500 mL ethyl acetate at 4 psi air pressure. Fractions 10-26 werecombined and evaporated in vacuo to afford 6.87 g of calcitriol as acolorless foam. Recrystallization from 30 mL of methyl formate afforded5.30 g of calcitriol as colorless needles, mp 110°-113°, [α]²⁰°D=+49.13° (c=1.0, Ethanol).

B. From1(S),3(R),25-Trihydroxy-9,10-seco-cholesta-5(E),7(E),10(19)-triene. A1.0 L, jacketed photochemical reaction was charged with 9.79 g of thecompound from Example 21 and 0.43 g of 9-acetylanthracene in 1.0 L ofmethanol. Argon was passed through the cooled (0° C.) solution andirradiation was carried out at 0°-5° C. with a medium pressure 450 WHanovia lamp through a uranium filter for 2.0 hours. The solution wastransferred to a 3-L, round-bottomed flask and was concentrated at 45°C. to give a foam. This was dissolved in 30 mL of 70% ethyl acetate inhexane and the solution was applied to a column of 180 g of silica gel(40 μm) packed in 70% ethyl acetate in hexane. Elution collecting 100-mLfractions, was carried out under pressure with 1 L of 70% ethyl acetatein hexane (to remove a small amount of non-polar material), 1 L of 80%ethyl acetate in hexane, and finally 1 L of 90% ethyl acetate in hexane.The progress of the chromatography was monitored by TLC (30% hexane inethyl acetate). The appropriate fractions were combined and evaporatedto give 10.17 g of a foam, which was crystallized from 220 mL of methylformate to give 6.5 g of calcitriol, mp 115°-116°C.; [α]²⁵ D+45.5°(EtOH, c=1.059).

We claim:
 1. A process for the preparation of a compound of the formula ##STR14## wherein A is a 23,24-bisnorsteroid or a 23,24-bisnor-9,10-secosteroid radical, R₁ is hydrogen, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyl or unsubstituted or substituted lower alkyl, and R₂ is hydroxyl, lower alkoxy, or unsubstituted or substituted lower alkyl,(1) which comprises reacting a compound of the formula ##STR15## with a nickel salt hydrate or, if unhydrated, in the presence of a proton source and a reducing agent; in the presence of an organic solvent and ligand source, and thereafter, (2) treating the reaction product of step 1, with a compound of the formula

    AX                                                         II

wherein A is as previously described, and X is halogen to yield the corresponding compound of formula IV.
 2. A process according to claim 1, wherein the nickel salt is nickel halide hydrate.
 3. A process according to claim 2, wherein the reducing agent is zinc.
 4. A process according to claim 3, wherein the compounds of formula II are ##STR16## wherein X is halogen, R₃ is hydrogen or OP and P is hydrogen or a protecting group.
 5. A process according to claim 4, wherein R₃ is hydrogen, X is iodine, and P is t-butyldimethylsilyl.
 6. A process according to claim 5, wherein the compound of formula III, R₁ is hydrogen and R₂ is lower alkyl or lower alkoxy. 